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With Persistence And Phase 3 Win, Amicus Nears First Drug Approval

Amicus Therapeutics was on the ropes in late 2012 when its pill for a rare condition called Fabry Disease failed a late-stage trial. It had already put seven years of work into the drug, and the setback added even more development time and uncertainty to the mix. But the Cranbury, NJ-based company kept plugging away, and now it looks like all the effort could lead to its first approved drug.

Amicus (NASDAQ: FOLD) is reporting today that the Fabry drug, migalastat, succeeded in the second of two late-stage trials. It hit two main goals that essentially measured its ability to slow the decline of Fabry patients’ kidney function comparably to enzyme-replacement therapy (ERT)—the standard of care for the often-fatal disorder.

Amicus believes the results, along with those from an earlier Phase 3 trial comparing migalastat to a placebo, are good enough to ask regulators in the U.S. and Europe for market approval.

“These are the good days to be a CEO,” says Amicus CEO John Crowley (pictured above). “It’s great when a plan comes together and data cooperates.”

Crowley says Amicus will seek approval of migalastat first in Europe and is already in talks with regulators there. In the next few months, Amicus will begin talking with the FDA about a path for approval in the U.S. as well.

Amicus will discuss the data in detail on a conference call this morning.

As I profiled in Xconomy last week, Amicus has taken a long, winding road to get to this point. Launched in 2002, the company has spent more than a decade trying to prove that “pharmacological chaperones”—small-molecule drugs designed to grab misfolded enzymes, force them into the correct shape, and shepherd them to the proper locations in a cell—could become effective therapies.

Amicus’s chaperones are designed to treat lysosomal storage disorders (LSDs). Fabry is one LSD. Pompe and Gaucher are two others, and they are all caused by mutations in the genetic instructions for important enzymes that normally help our cells clear out “waste”—extra fats and sugars, for example. But genetic defects mean those enzymes are folded into the wrong shape and don’t function properly, or they’re missing altogether. The waste instead builds up and causes serious damage.

There are no cures for these disorders. They’re often treated with ERT, which replaces the missing or faulty enzymes with genetically engineered, working ones that need to be infused into the patient every few weeks.

Amicus believes its chaperones can replace ERT in some instances, and boost ERT’s effectiveness in others. But the company has seen its share of setbacks. First, a drug for Gaucher flopped in 2009. Then in 2012, migalastat missed its goal in the first stage of the Phase 3 trial it’s been running in the U.S.

The migalastat program was teetering at that point, but Amicus dug through the data and found that patients with so-called “amenable mutations,” representing about 30 to 50 percent of the Fabry population, were responding better. Amicus pleaded with the FDA to change the clinical goals for its trial to incorporate its discovery.

The agency said yes, but noted the failure would stay on Amicus’s record, and that the company now had to submit data both from its U.S. trial and the Europe study, which wasn’t required before. Amicus considered dumping the program, but instead doubled down. It reacquired worldwide rights to the drug from former partner GlaxoSmithKline, which also meant it would shoulder all the development costs.

The retooled U.S. study, which compared migalastat to a placebo, first produced positive data in April, sending Amicus’ shares up more than 25 percent. The European study required a bit more logistical planning—Amicus, after all, had to convince doctors to take patients with a potentially fatal condition off an approved therapy and try an experimental drug instead. Amicus also had to go head to head with ERT, not just a placebo.

In the European study, Amicus took a group of 60 patients who’d been on ERT for at least a year, switched 34 of them to migalastat, and compared them to 26 who remained on ERT. Amicus tracked both groups for 18 months, aiming to show that by two statistical measures of kidney function, migalastat was comparable (not superior) to ERT for those that have amenable mutations.

Amicus said today that it’s succeeded on both of those measures and further, that almost all of the patients with amenable mutations who completed the Europe study chose to remain on migalastat for another 12 months as part of an extension study.

“It looks statistically indistinguishable from those that were on ERT,” says Raphael Schiffmann, an investigator in the study at Baylor’s Institute of Metabolic Disease. That therapeutic parity could be particularly useful for early-stage Fabry patients who want to avoid starting up with ERT.

The results are promising, but Schiffman cautions that this is the “beginning of the story.” It’s unclear, for instance, how migalastat’s effects will hold up over a longer period of time compared to ERT—say, for a child who begins taking it as a lifelong therapy.

Those are questions Amicus will have to answer down the road. For now, the main question is whether regulators will approve migalastat based on the data it’s accrued. Crowley says he’d be “very much surprised” if the FDA requires another study.

Amicus will argue for migalastat’s safety (it’s been well tolerated), its convenience (patients take a pill instead of bi-monthly trips to the infusion center), and potentially its cost. ERT costs about $300,000 per year, per patient. Crowley says migalastat would likely be expensive, as well, but it could be “better priced” than ERT.

“If we can deliver a comparable therapy that’s more effective with a better safety profile that’s also better priced without hospital and infusion costs, I think that’s a real win all around for the system,” he says.

Ben Fidler is Xconomy's Deputy Editor, Biotechnology. You can e-mail him at bfidler@xconomy.com Follow @benthefidler